Human cancers frequently express tumor associated antigens (TAAs) that are altered forms of self-proteins or epitopes with very limited or no expression on normal cells. Over the past few decades, the list of known TAAs has greatly increased (Vigneron N. et al., Cancer Immun 13:15 (2013)). Interestingly, because the immune surveillance system is continuously exposed to self-antigens, T cells that recognize high-affinity, major histocompatibility complex (MHC)-associated immunodominant epitopes get deleted through a thymic selection process. On the other hand, T cells that recognize low-affinity subdominant epitopes of TAAs are left behind during the selection process. These T cells, which recognize subdominant epitopes of self-proteins, can be recruited by vaccination for the induction of an immune response (Cibotti R. et al., Proc Natl Acad Sci USA, 416-20 (1992)). Simply described, these TAAs are recognized by the host immune system as foreign, resulting in an antitumor immune response.
Over the years, identification of several TAAs has spurred the development of cancer vaccines and active specific immunotherapies for cancer designed to boost an immune response. Cancer vaccines offer a new therapeutic direction by inducing an immune response that can persist long after the vaccine therapy has been discontinued. In contrast, chemotherapy and small, targeted molecules directly affect tumor cells only during the period of administration. Furthermore, cancer vaccines can theoretically induce a more robust immune response with minimal toxicity.
In recent years, multiple studies have demonstrated that cellular [T helper type 1 (TH1) and cytotoxic T lymphocyte (CTL)-mediated] rather than humoral [T helper type 2 (TH2) antibody-mediated] immune responses are responsible for the rejection of transplanted tumors or allogeneic tissues in experimental animal models (Kirkwood J M. et al., CA Cancer J Clin., 62:309-35 (2012); Melero I. et al., Nat Rev Clin Oncol. 11:509-24 (2014); Rosenberg S A., Nature., 411:380-4 (2001)). A TH1-polarized immune response involving CTLs and natural killer (NK) cells mediates the elimination of tumor cells, while a TH2-polarized immune response can have deleterious effects by promoting tumor development and progression (Kirkwood J M. et al., CA Cancer J Clin., 62:309-35 (2012); Curigliano G. et al., Breast., 22 Suppl 2:S96-9 (2013)). Therefore, significant efforts have been directed toward the identification of TAAs recognized by human T lymphocytes to mount a cellular immune response (Boon T. et al., Immunol Today., 18:267-8 (1997); Rosenberg S A., Immunity, 10:281-7 (1999)). This is not to say that antibody-based anticancer immunotherapies are ineffective against solid tumors. Indeed, the past decade has seen the clinical development of numerous monoclonal antibodies directed at growth factors such as vascular endothelial growth factor (VEGF), growth factor receptors such as human epidermal growth factor receptor (EGFR) and negative immune checkpoint regulators such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death receptor 1 (PD-1) (Sliwkowski M X. et al., Science., 341:1192-8 (2013)).
Although chemotherapy has been traditionally believed to antagonize immunotherapy, it is now becoming apparent that conventional chemotherapy has significant “off-target” immunological effects (Kandalaft L E. et al., Gynecol Oncol., 116:222-33 (2010)). Earlier studies have clearly highlighted the role of the immune system in cancer clearance. In mouse models of solid tumors, increased inflammation following chemotherapy predicts better prognosis (Kepp 0. et al., Apoptosis, 14:364-75 (2009)), while tumors in immunodeficient mice do not respond to the chemotherapy (Obeid M. et al., Cancer Res., 67:7941-4 (2007)). Similarly, the presence of tumor-infiltrating lymphocytes (TIL) in breast cancer patients following neo-adjuvant chemotherapy predicted complete pathological response (Hornychova H. et al., Cancer Invest. 26:1024-31 (2008)).
Tumor inflammation has been shown to be involved in many stages of tumor development and progression (Grivennikov S I. et al., Cell, 140:883-99 (2010)). The influence of inflammation on the immune system's response to tumors, in conjunction with its known tumorigenic properties, can potentially be utilized in cancer immunotherapy (Dougan M. et al., Annu Rev Immunol., 27:83-117 (2009)) and enhance the response to chemotherapy (Zhu Z. et al., Mediators Inflamm., 2012:528690 (2012); Zitvogel L. et al., Nat Rev Immunol., 8:59-73 (2008)). However, the antitumor effects of cancer chemotherapy can also be weakened by inflammation (Ammirante M. et al., Nature, 464:302-5 (2010)). Thus, cancer-related inflammation remains a target for novel therapeutic strategies.
To summarize, the identification of TAAs in various cancers has made the development of cancer immunotherapies an attractive area of pharmaceutical research. The efficacy of chemotherapy is known to be affected by inflammation, which is also a target for novel therapeutic strategies. Agents that can regulate the inflammatory microenvironment created by tumorigenesis and chemotherapy may improve the response to both antigen-specific cancer immunotherapies and chemoradiotherapy through immunomodulation.
With respect to infectious disease, intense efforts are currently underway to develop effective vaccines and other immunotherapies to combat viral infections such as Ebola virus. According to the latest data from the World Health Organization, the current (2014-15) epidemic of Ebola virus disease, formerly known as Ebola hemorrhagic fever, in western Africa had claimed more than 11,000 lives as of early November 2015. Several different strategies, including monoclonal antibodies (Qiu X. et al., Nature, 514:47-53 (2014)), RNA interference (Geisbert T W. et al., Lancet., 375:1896-905 (2010)), and a bivalent vaccine based on the rabies virus vaccine (Blaney J E. et al., PLoS Pathog., 9:e1003389 (2013)), have been studied, and several Phase I clinical trials are already underway or are planned in the near future. The symptoms associated with a fatal outcome in an Ebola virus infection are a poorly regulated inflammatory immune response coupled with immune suppression. Accordingly, agents that can regulate the inflammatory response of the immune system may improve the response to the therapeutic agents through immunomodulation. Identification of such agents could improve the survival rate of Ebola virus infections and similar diseases.
Additionally, it is known that the immune response in people aged 50 and older, and especially in those aged 65 and over, is generally weaker compared to younger subjects due to the phenomenon known as immunosenescence (Goronzy J. et al., Nat. Immunol., 14:428-36 (2013)). This results in a reduced ability to mount an effective immune response against infection as well as the vaccines used to prevent such infections. Thus, the identification of agents that can augment the immune response in older or immunocompromised individuals suffering from various viral, bacterial, or other infectious diseases is desirable.
As such, there is a need in the art for agents that can modulate an immune response to a therapeutic agent in a subject. The present invention addresses this need and provides related advantages as well.